The present invention relates generally to the detection of nitric oxide in a gaseous mixture and, more specifically, to the detection of nitric oxide in a flow pathway.
Definition of Nitric Oxide
Nitric oxide, NO, is a colorless gas useful in the detection and treatment of a variety of medical conditions such as asthma. Nitric oxide, NO, should not be confused with nitrous oxide, N2O, or nitrogen dioxide, NO2. Nitrogen and oxygen also form other compounds, especially during combustion processes. These typically take the form of NOx where x represents an integer. These forms are generally referred to as NOX. Detection of nitric oxide, NO, is the primary focus of the present application. Nitric oxide has a variety of beneficial uses and detection of nitric oxide, especially in small concentrations, is necessary for the proper administration of nitric oxide and diagnosis of disease.
Use of Nitric Oxide in Treatment of Physiological Conditions
Nitric oxide is beneficial in both the treatment and diagnosis of asthma and other forms of lung disorders. Asthma is a chronic disease characterized by intermittent, reversible, widespread constriction of the airways of the lungs in response to any of a variety of stimuli that do not affect the normal lung. A variety of drugs are commonly used to treat asthma. It is known that inhalation of nitric oxide (NO) is therapeutically beneficial in the prevention and treatment of asthma attacks and other forms of bronchoconstriction, of acute respiratory failure, or of reversible pulmonary vasoconstriction as discussed in U.S. Pat. No. 5,873,359 to Zapol et al, incorporated herein by reference. U.S. Pat. Nos. 5,904,938 and 6,063,407, both to Zapol et al. and incorporated herein by reference, disclose the use of inhaled nitric oxide in the treatment of vascular thrombosis and retinosis. Typically, treatment utilizing nitric oxide includes the introduction of nitric oxide as a portion of the respiratory gases being inhaled by the patient. The nitric oxide concentration is usually in the range of 1 to 180 parts per million (ppm). The difficulty presented in the administration of controlled amounts of nitric oxide is the determination of the concentration being introduced. It has traditionally been very difficult to quickly and accurately determine the concentration of nitric oxide in the gas mixture, especially where the concentration of nitric oxide is very low.
U.S. Pat. No. 5,839,433 to Higenbottam, incorporated herein by reference, describes the use of nitric oxide in the treatment of certain lung diseases and conditions. As discussed in the specification, a drawback to the administration of gaseous nitric oxide is that it rapidly converts to nitrogen dioxide, a potentially harmful substance. Consequently, it is often preferable to intubate the patient so that nitric oxide is administered directly to the lungs. Whether or not intubated, it is very important to accurately monitor the amount of nitric oxide being introduced to the lungs. The Higenbottam reference proposes an improvement wherein the nitric oxide is introduced as a short pulse of known volume, rather than continuously during inhalation.
U.S. Pat. No. 5,531,218 to Krebs, incorporated herein by reference, discusses the benefits of nitric oxide inhalation in the treatment of various disorders, including adult respiratory distress syndrome, (ARDS). The specification discloses a system for administering nitric oxide that includes a source of nitric oxide, an analyzer for analyzing nitric oxide concentration, and a control unit, with the analyzer and the control unit cooperating to maintain the appropriate nitric oxide concentration. However, this system relies on the use of nitric oxide sensors utilizing infrared absorption measurement, electrochemical sensors, or chemiluminescence detectors. Each of these analyzers have drawbacks and cannot provide instantaneous nitric oxide concentration measurements.
Use of Nitric Oxide in Diagnosis
Nitric oxide may also be used in the diagnosis of various physiological conditions. For example, the reversibility of chronic pulmonary vasorestriction may be diagnosed by administering known quantities of nitric oxide and monitoring changes in pulmonary arterial pressure (PAP) and cardiac output as described in U.S. Pat. No. 5,873,359 to Zapol et al.
Endogenous production of nitric oxide in the human airway has been shown to be increased in patients with asthma and other inflammatory lung diseases. Expired nitric oxide concentrations are also elevated in patients with reactive airways disease. Therefore, detection of nitric oxide is beneficial in diagnosing these conditions. However, proper diagnosis requires accurate measurement of nitric oxide in parts per billion (ppb) of gas-phase nitric oxide.
Determination of the level of nitric oxide is useful in the diagnosis of inflammatory conditions of the airways, such as allergic asthma and rhinitis, in respiratory tract infections in humans and Kartagener""s syndrome. It also has been noted that the level of nitric oxide in the exhalation of smokers is decreased. U.S. Pat. No. 5,922,610 to Alving et al., incorporated herein by reference, discusses the detection of nitric oxide in diagnosing these conditions, as well as gastric disturbances.
In addition to the above, nitric oxide may be used in the determination of lung function. For example, U.S. Pat. No. 5,447,165 to Gustafsson, incorporated herein by reference, explains that nitric oxide in exhalation air is indicative of lung condition. As one test of lung function, a subject may inhale a trace gas, such as nitric oxide. Then the concentration and time-dispersment of the gas in the exhalation air is measured. The shape of the curve representing the time dependent gas concentration in the exhalation air is indicative of lung function or condition. Obviously, it is necessary to have an accurate determination of both the concentration and the time-dependence of the concentration to allow for the most accurate diagnosis.
During exhalation, gas mixture changes during the breath. The initial portion of the exhalation is xe2x80x9cdead spacexe2x80x9d air that has not entered the lungs. This includes the respiratory gases in the mouth and respiratory passages above the lungs. Also, some portion of the exhalation measured by an analytical instrument may be attributed to dead air in the mask and flow passages of the apparatus. As a breath continues, respiratory gases from within the lungs are exhaled. The last portion of respiratory gases exhaled is considered alveolar air. Often it is beneficial to measure gas concentrations in alveolar air to determine various pulmonary parameters. For example, nitric oxide, as an indicator of various disease states, may be concentrated in the alveolar air. However, nitric oxide is also produced by various mucus membranes and therefore nitric oxide may be present in both the dead air space and in the alveolar air. During an exhalation, the dead air space may be overly contaminated with nitric oxide due to residence in the mouth and nasal cavities where nitric oxide is absorbed from the mucus membranes. Therefore, it is necessary to distinguish the various portions of exhalation for proper diagnosis. U.S. Pat. No. 6,038,913 to Gustafsson et al., incorporated herein by reference, discusses having an exhalation occur with very little resistance during an initial xe2x80x9cdead spacexe2x80x9d phase of exhalation and then creating resistance against the remaining portion of the exhalation.
Nitric Oxide Measurement Methods
Numerous approaches have been used and proposed for monitoring the concentration of nitric oxide in a gas mixture. These include mass spectroscopy, electrochemical analysis, calorimetric analysis, chemiluminescence analysis, and piezoelectric resonance techniques. Each of these approaches have shortcomings that make them poorly suited to widespread use in the diagnosis and treatment of disease.
Mass spectroscopy utilizes a mass spectrometer to identify particles present in a substance. The particles are ionized and beamed through an electromagnetic field. The manner in which the particles are deflected is indicative of their mass, and thus their identity. Mass spectroscopy is accurate but requires the use of very expensive and complicated equipment. Also, the analysis is relatively slow, making it unsuitable for real time analysis of exhalations. Preferably, in the breath by breath analysis of nitric oxide, it is desirable to quickly and accurately measure the nitric oxide concentration in the flow path as the gas mixture flows through the flow path. Mass spectroscopy requires sampling of portions of the gas mixture rather than analyzing the nitric oxide concentration in the flow pathway itself. Mass spectroscopy cannot be considered an instantaneous or continuous analysis approach. It requires dividing the exhalation into multiple discrete samples and individual analysis of each sample. This does not create a curve of the nitric oxide concentration but instead creates a few discreet points. Sampling-based systems are especially deficient when detecting gases in very low concentrations since large samples are required.
Electrochemical-based analysis systems use an electrochemical gaseous sensor in which gas from a sample diffuses into and through a semi-permeable barrier, such as membrane, then through an electrolyte solution, and then to one of typically three electrodes. At one of the three electrodes, a sensing redox reaction occurs. At the second, counter, electrode, a complimentary and opposite redox reaction occurs. A third electrode is typically provided as a reference electrode. Upon oxidation, or reduction, of the nitric oxide at the sensing electrode, a current flows between the sensing and counter electrode that is proportional to the amount of nitric oxide reacting at the sensing electrode surface. The reference electrode is used to maintain the sensing electrode at a fixed voltage. A typical electrochemical-based gas analyzer for detecting nitric oxide is shown is U.S. Pat. No. 5,565,075 to Davis et al, incorporated herein by reference. Electrochemical-based devices have high sensitivity and accuracy, but typically have a response time in excess of 30 seconds. This is significantly too slow to allow breath by breath, or continuous, analysis of respiration gases.
Colorimetric analysis relies on a chemical reaction by a gas which provides a corresponding change in pH, thereby triggering a color change in an indicator. This approach requires expendable chemical substances. Also, this approach is often disturbed by the presence of other gases, particularly the relative amount of humidity present. Response times are too slow for analysis during a breath.
Chemiluminescent-based devices depend on the oxidation of nitric oxide by mixing the nitric oxide with ozone, O3, to create nitrogen dioxide and oxygen. The nitrogen dioxide is in an excited state immediately following the reaction and releases photons as it decays back to a non-excited state. By sensing the amount of light emitted during this reaction, the concentration of nitric oxide maybe determined. An example of a chemiluminescent-based device is shown in U.S. Pat. No. 6,099,480 to Gustafsson, incorporated herein by reference. Chemiluminescent devices have response times as fast as about two hundred milliseconds, have high sensitivity, repeatability, and accuracy. However, like with mass spectroscopy, and electrochemical analysis, chemiluminescent analysis requires sampling of the gas mixture rather than continuous analysis of the gas concentration in the flow path itself. Also, chemiluminescent devices are typically very large and expensive.
Piezoelectric resonance techniques are sometimes referred to as MEMS (microelectro-mechanical systems) sensor devices. Basically, a micro-etched cantilevered beam is coated with a xe2x80x9ccapturexe2x80x9d molecule that is specific to the gas being analyzed. In theory, the capture molecule will capture the gas being analyzed in proportion to its ambient concentration. This alters the mass of the micro-etched cantilevered beam. Changes in mass of the beam may theoretically be detected based on changes in its resonant frequency. The change in resonant frequency should be directly proportional to the concentration of the gas being studied. A system for detecting air pollutants is disclosed in U.S. Pat. No. 4,111,036 to Frechette et al., incorporated herein by reference. While the theory behind piezoelectric resonance techniques is rather simple, there has been no known success to date in the analysis of nitric oxide concentrations.
U.S. Pat. No. 6,033,368 to Gaston IV et al. discloses an analyzer for measuring exhaled nitrogen oxides, nitrite and nitrate in very low concentrations. The analyzer includes a chilled exhalation passage which causes lung fluid vapors to collect. The resulting liquid is then analyzed using standard calorimetric assays. While somewhat simpler than other methods, the Gaston apparatus remains complicated, requiring prefreezing of the chilling apparatus, and subsequent analysis of the collected liquid.
Each of the above-described approaches for the use and detection of nitric oxide would benefit from a nitric oxide meter capable of continuously determining the nitric oxide concentration of a flow of respiratory gases in a flow pathway without the need for sampling the mixture. Most preferably, such a meter would provide nearly instantaneous response times so that analysis may be made during a breath or on a breath-by-breath basis.
The present invention overcomes many of the shortcomings of the prior art by providing a nitric oxide meter designed to provide continuous, or breath-by-breath, analysis. The nitric oxide meter includes a respiratory connector designed to be supported in contact with a subject so as to pass respiratory gases when the subject breathes. A flow pathway receives and passes respiration gases. One end of the flow pathway has in fluid communication with the respiratory connector, and the other end is in fluid communication with a source and sink of respiratory gases. A nitric oxide concentration sensor generates electrical signals as a function of the instantaneous fraction of nitric oxide in the respiration gases as the gases pass through the flow pathway. In some embodiments of the present invention, a flow meter is also provided in the respiratory nitric oxide meter. The flow meter may be an ultrasonic flow meter including a pair of spaced-apart ultrasonic transducers. In other embodiments of the present invention, the respiratory nitric oxide meter forms part of a system for the controlled administration of nitric oxide to the subject. This system includes a nitric oxide regulator designed to selectively introduce nitric oxide into inhalation gases in the pathway. The system may also include a controller which controls the regulator based on signals received from the nitric oxide concentration sensor so as to maintain the instantaneous fraction of nitric oxide in the inhalation gases within prescribed limits.
According to one aspect of the present invention, there is provided a respiratory nitric oxide meter for measuring the nitric oxide content of respiration gases for a subject, said meter comprising: a respiratory connector configured to be disposed in fluid communication with the respiratory system of the subject so as to pass inhalation and exhalation respiratory gases as the subject breathes; a flow pathway operable to receive and pass the respiration gases, the flow pathway having a first end in fluid communication with the respiratory connector and a second end in fluid communication with a reservoir of respiratory gases; a nitric oxide concentration sensor operable to generate electrical signals as a function of the instantaneous fraction of nitric oxide in the respiration gases as the gases pass through the flow pathway; and a one-way valve located between the respiratory connector and the first end of the flow pathway. The one-way valve is presettable in a first position effective to pass inhalation gases directly into the respiratory connector bypassing the flow pathway, and to pass exhalation gases through the flow pathway so as to contact the nitric oxide concentration sensor, to thereby sense the nitric oxide concentration in the exhalation gases. The one-way valve is also presettable in a second position effective to pass exhalation gases directly from the respiratory connector bypassing the flow pathway, and to pass inhalation gases through the flow pathway so as to contact the nitric oxide concentration sensor, to thereby sense the nitric oxide concentration in the inhalation gases.
The reservoir of respiratory gases may be the atmosphere, or another separate source of respiratory gases.
According to another aspect of the present invention, there is provided a respiratory nitric oxide meter for measuring the nitric oxide content of respiration gases for a subject, the meter comprising: a respiratory connector configured to be disposed in fluid communication with the respiratory system of the subject so as to pass exhalation respiration gases as the subject breathes; a flow pathway operable to receive and pass the exhalation respiration gases, the pathway having a first end in fluid communication with the respiratory connector and a second end in fluid communication with a reservoir of respiratory gases; a flow meter configured to generate electrical signals as a function of the instantaneous flow of respiration gases passing through the flow pathway; and a nitric oxide concentration sensor operable to generate electrical signals as a function of the instantaneous fraction of nitric oxide in the exhalation respiration gases as the gases pass through the flow pathway; the nitric oxide concentration sensor having a response time of less than 200 ms to enable instantaneous analysis of the exhalation respiratory gases during a single breath.
Further features of the invention will be apparent from the description below.